scholarly journals Variation in olfactory neuron repertoires is genetically controlled and environmentally modulated

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ximena Ibarra-Soria ◽  
Thiago S Nakahara ◽  
Jingtao Lilue ◽  
Yue Jiang ◽  
Casey Trimmer ◽  
...  
Keyword(s):  
Olfactory Receptor ◽  
Sensory System ◽  
Dependent Manner ◽  
Olfactory Neuron ◽  
Neuronal Diversity ◽  
Cis Acting ◽  
Genetic And Environmental Factors ◽  
Or Gene ◽  
Different Strains ◽  
Subtype Distribution

The mouse olfactory sensory neuron (OSN) repertoire is composed of 10 million cells and each expresses one olfactory receptor (OR) gene from a pool of over 1000. Thus, the nose is sub-stratified into more than a thousand OSN subtypes. Here, we employ and validate an RNA-sequencing-based method to quantify the abundance of all OSN subtypes in parallel, and investigate the genetic and environmental factors that contribute to neuronal diversity. We find that the OSN subtype distribution is stereotyped in genetically identical mice, but varies extensively between different strains. Further, we identify cis-acting genetic variation as the greatest component influencing OSN composition and demonstrate independence from OR function. However, we show that olfactory stimulation with particular odorants results in modulation of dozens of OSN subtypes in a subtle but reproducible, specific and time-dependent manner. Together, these mechanisms generate a highly individualized olfactory sensory system by promoting neuronal diversity.

scholarly journals OR1D2 receptor mediates bourgeonal-induced human CatSper activation in a G-protein dependent manner

2019 ◽  
Author(s):  
Yi-min Cheng ◽  
Tao Luo ◽  
Zhen Peng ◽  
Hou-yang Chen ◽  
Jin Zhang ◽  
...  
Keyword(s):  
G Protein ◽  
Olfactory Receptor ◽  
Intracellular Signaling ◽  
Calcium Influx ◽  
Human Sperm ◽  
Camp Level ◽  
Dependent Manner ◽  
Intracellular Signaling Pathway ◽  
Camp Pathway ◽  
Sperm Chemotaxis

AbstractDuring fertilization, sperm are guided towards eggs by physiological chemokines, a process named sperm chemotaxis. Human sperm chemotaxis is speculated to be mediated by olfactory receptor OR1D2 in a pathway requiring calcium influx. Bourgeonal, an artificial ligand of OR1D2, can activate CatSper, the primary calcium channel in human sperm. However, whether bourgeonal-induced CatSper activation requires OR1D2 and how CatSper is activated remain unclear. Herein, we show that OR1D2 antibody can inhibit bourgeonal-induced CatSper activation and sperm chemotaxis, proving that OR1D2 mediates bourgeonal-induced CatSper activation. Furthermore, bourgeonal-evoked CatSper currents can be greatly suppressed by either GDP-β-S or antibody of Gαs. Interestingly, bourgeonal can transiently increase sperm cAMP level, and this effect can be abolished by OR1D2 antibody. Consistently, bourgeonal-induced CatSper activation can be inhibited by membrane adenylate cyclases inhibitor. Overall, our results indicate that bourgeonal activates CatSper via OR1D2-G protein-cAMP pathway. Although CatSper can be activated by various physiological and environmental factors, this study represents the most recent progress proving that CatSper can be indirectly activated by extracellular regulators through a G-protein-dependent intracellular signaling pathway.

scholarly journals MHC-Linked Olfactory Receptor Loci Exhibit Polymorphism and Contribute to Extended HLA/OR-Haplotypes

2000 ◽  
Vol 10 (12) ◽  
pp. 1968-1978 ◽  
Author(s):  
Anke Ehlers ◽  
Stephan Beck ◽  
Simon A. Forbes ◽  
John Trowsdale ◽  
Armin Volz ◽  
...  
Keyword(s):  
Olfactory Receptor ◽  
Sequence Data ◽  
Allelic Variation ◽  
Mate Preferences ◽  
Coding Region ◽  
Link Type ◽  
Or Gene ◽  
Hla Haplotypes ◽  
A Minor ◽  
Or Genes

Clusters of olfactory receptor (OR) genes are found on most human chromosomes. They are one of the largest mammalian multigene families. Here, we report a systematic study of polymorphism of OR genes belonging to the largest fully sequenced OR cluster. The cluster contains 36 OR genes, of which two belong to the vomeronasal 1 (V1-OR) family. The cluster is divided into a major and a minor region at the telomeric end of the HLA complex on chromosome 6. These OR genes could be involved in MHC-related mate preferences. The polymorphism screen was carried out with 13 genes from the HLA-linked OR cluster and three genes from chromosomes 7, 17, and 19 as controls. Ten human cell lines, representing 18 different chromosome 6s, were analyzed. They were from various ethnic origins and exhibited different HLA haplotypes. All OR genes tested, including those not linked to the HLA complex, were polymorphic. These polymorphisms were dispersed along the coding region and resulted in up to seven alleles for a given OR gene. Three polymorphisms resulted either in stop codons (genes hs6M1-4P,hs6M1-17) or in a 16–bp deletion (gene hs6M1-19P), possibly leading to lack of ligand recognition by the respective receptors in the cell line donors. In total, 13 HLA-linked OR haplotypes could be defined. Therefore, allelic variation appears to be a general feature of human OR genes.[The sequence data reported in this paper have been submitted to EMBL under accession nos. AC006137, AC004178, AJ132194, AL022727, AL031983,AL035402, AL035542, Z98744, CAB55431, AL050339, AL035402, AL096770,AL133267, AL121944, Z98745, AL021808, and AL021807.]

Proximal cis-acting elements cooperate to set Hoxb-7 (Hox-2.3) expression boundaries in transgenic mice

Development ◽  
1993 ◽  
Vol 118 (1) ◽  
pp. 71-82 ◽  
Author(s):  
R. Vogels ◽  
J. Charite ◽  
W. de Graaff ◽  
J. Deschamps
Keyword(s):  
Gene Expression ◽  
Expression Pattern ◽  
Hox Genes ◽  
Gene Clustering ◽  
Lacz Gene ◽  
Dependent Manner ◽  
Endogenous Gene ◽  
Cis Acting ◽  
Gene Map ◽  
Partial Overlap

The Hox genes have been proved to be instrumental in establishing the positional identity of cells along the embryonic anteroposterior (A-P) axis. Studying the regulation of these genes is a first step toward elucidating the molecular basis of regionalization during embryogenesis. We report here on the identification of cis-acting elements controlling the expression of Hoxb-7 (Hox-2.3). We show that elements driving A-P restricted gene expression are located within the 3.5 kb proximal upstream sequences of the Hoxb-7 gene. A deletion analysis provides evidence for at least three cis-acting control elements upstream from Hoxb-7, and for cooperative interactions between some of these elements in generating the A-P restricted transgenic pattern. One element, conferring by itself Hox-like expression boundaries to the transgene, has been studied in more detail and found to act in an orientation-and promoter-dependent manner. Together the 3.5 kb sequences proximal to Hoxb-7 mediate A-P restricted Hoxb-7/lacZ gene expression in a domain showing rostral boundaries more posterior than those of Hoxb-7. The evolution throughout embryogenesis of the expression pattern of a transgene carrying these sequences has been analysed and shown to mimick that of the endogenous gene, except for a slight delay in the initial expression. We conclude that the transgenes that we tested, spanning a total of 27 kb genomic sequences, do not reproduce all the features of the Hoxb-7 expression pattern. The differences in expression between Hoxb-7 and the transgenes may reveal an aspect of the Hox regulation for which either remote cis-acting control elements and/or gene clustering is required. Additional features that may have favoured maintenance of clustered organisation during evolution are partial overlap of transcription units with the regulatory regions of the neighbouring genes, and cis-regulatory interactions between multiple Hox genes: not only do cis-acting control elements of the Hoxb-7 gene map in the 3′ untranslated sequences of the Hoxb-8 (Hox-2.4) gene, but our experiments suggest that Hoxb-7 control sequences modulate expression of the Hoxb-8 gene as well.

Characterisation of cis-acting sequences reveals a biphasic, axon-dependent regulation of Krox20 during Schwann cell development

Development ◽  
2002 ◽  
Vol 129 (1) ◽  
pp. 155-166 ◽  
Author(s):  
Julien Ghislain ◽  
Carole Desmarquet-Trin-Dinh ◽  
Martine Jaegle ◽  
Dies Meijer ◽  
Patrick Charnay ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Schwann Cell ◽  
Dependent Manner ◽  
Cis Acting ◽  
Pou Domain ◽  
Cell Element ◽  
Schwann Cell Development ◽  
Myelinating Schwann Cell ◽  
Sciatic Nerve Regeneration

In Schwann cells (SC), myelination is controlled by the transcription factor gene Krox20/Egr2. Analysis of cis-acting elements governing Krox20 expression in SC revealed the existence of two separate elements. The first, designated immature Schwann cell element (ISE), was active in immature but not myelinating SC, whereas the second, designated myelinating Schwann cell element (MSE), was active from the onset of myelination to adulthood in myelinating SC. In vivo sciatic nerve regeneration experiments demonstrated that both elements were activated during this process, in an axon-dependent manner. Together the activity of these elements reproduced the profile of Krox20 expression during development and regeneration. Genetic studies showed that both elements were active in a Krox20 mutant background, while the activity of the MSE, but likely not of the ISE, required the POU domain transcription factor Oct6 at the time of myelination. The MSE was localised to a 1.3 kb fragment, 35 kb downstream of Krox20. The identification of multiple Oct6 binding sites within this fragment suggested that Oct6 directly controls Krox20 transcription. Taken together, these data indicate that, although Krox20 is expressed continuously from 15.5 dpc in SC, the regulation of its expression is a biphasic, axon-dependent phenomenon involving two cis-acting elements that act in succession during development. In addition, they provide insight into the complexity of the transcription factor regulatory network controlling myelination.

scholarly journals Susceptibility of Candida Species to Photodynamic Effects of Photofrin

2004 ◽  
Vol 48 (6) ◽  
pp. 2000-2006 ◽  
Author(s):  
Joseph M. Bliss ◽  
Chad E. Bigelow ◽  
Thomas H. Foster ◽  
Constantine G. Haidaris
Keyword(s):  
Photodynamic Therapy ◽  
Drug Dose ◽  
Culture Conditions ◽  
Dependent Manner ◽  
In Vitro Susceptibility ◽  
Therapeutic Modalities ◽  
Fungal Damage ◽  
Different Strains ◽  
Photosensitizing Agent

ABSTRACT The in vitro susceptibility of pathogenic Candida species to the photodynamic effects of the clinically approved photosensitizing agent Photofrin was examined. Internalization of Photofrin by Candida was confirmed by confocal fluorescence microscopy, and the degree of uptake was dependent on incubation concentration. Uptake of Photofrin by Candida and subsequent sensitivity to irradiation was influenced by culture conditions. Photofrin uptake was poor in C. albicans blastoconidia grown in nutrient broth. However, conversion of blastoconidia to filamentous forms by incubation in defined tissue culture medium resulted in substantial Photofrin uptake. Under conditions where Photofrin was effectively taken up by Candida, irradiated organisms were damaged in a drug dose- and light-dependent manner. Uptake of Photofrin was not inhibited by azide, indicating that the mechanism of uptake was not dependent on energy provided via electron transport. Fungal damage induced by Photofrin-mediated photodynamic therapy (PDT) was determined by evaluation of metabolic activity after irradiation. A strain of C. glabrata took up Photofrin poorly and was resistant to killing after irradiation. In contrast, two different strains of C. albicans displayed comparable levels of sensitivity to PDT. Furthermore, a reference strain of C. krusei that is relatively resistant to fluconazole compared to C. albicans was equally sensitive to C. albicans at Photofrin concentrations of ≥3 μg/ml. The results indicate that photodynamic therapy may be a useful adjunct or alternative to current anti-Candida therapeutic modalities, particularly for superficial infections on surfaces amenable to illumination.

scholarly journals Ornithine decarboxylase mRNA is stabilized in an mTORC1-dependent manner in Ras-transformed cells

2012 ◽  
Vol 442 (1) ◽  
pp. 199-207 ◽  
Author(s):  
Sofia Origanti ◽  
Shannon L. Nowotarski ◽  
Theresa D. Carr ◽  
Suzanne Sass-Kuhn ◽  
Lan Xiao ◽  
...  
Keyword(s):  
Ornithine Decarboxylase ◽  
Translation Initiation ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Regulatory Sequences ◽  
Minor Effect ◽  
Dependent Manner ◽  
Cis Acting ◽  
Treatment And Prevention ◽  
Effector Pathways

Upon Ras activation, ODC (ornithine decarboxylase) is markedly induced, and numerous studies suggest that ODC expression is controlled by Ras effector pathways. ODC is therefore a potential target in the treatment and prevention of Ras-driven tumours. In the present study we compared ODC mRNA translation profiles and stability in normal and Ras12V-transformed RIE-1 (rat intestinal epithelial) cells. While translation initiation of ODC increased modestly in Ras12V cells, ODC mRNA was stabilized 8-fold. Treatment with the specific mTORC1 [mTOR (mammalian target of rapamycin) complex 1] inhibitor rapamycin or siRNA (small interfering RNA) knockdown of mTOR destabilized the ODC mRNA, but rapamycin had only a minor effect on ODC translation initiation. Inhibition of mTORC1 also reduced the association of the mRNA-binding protein HuR with the ODC transcript. We have shown previously that HuR binding to the ODC 3′UTR (untranslated region) results in significant stabilization of the ODC mRNA, which contains several AU-rich regions within its 3′UTR that may act as regulatory sequences. Analysis of ODC 3′UTR deletion constructs suggests that cis-acting elements between base 1969 and base 2141 of the ODC mRNA act to stabilize the ODC transcript. These experiments thus define a novel mechanism of ODC synthesis control. Regulation of ODC mRNA decay could be an important means of limiting polyamine accumulation and subsequent tumour development.

scholarly journals Met31p and Met32p, two related zinc finger proteins, are involved in transcriptional regulation of yeast sulfur amino acid metabolism.

1997 ◽  
Vol 17 (7) ◽  
pp. 3640-3648 ◽  
Author(s):  
P L Blaiseau ◽  
A D Isnard ◽  
Y Surdin-Kerjan ◽  
D Thomas
Keyword(s):  
Transcriptional Regulation ◽  
Amino Acid ◽  
Zinc Finger ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Dependent Manner ◽  
Sulfur Amino Acid ◽  
Cis Acting ◽  
The One ◽  
Methionine Transport

Sulfur amino acid metabolism in Saccharomyces cerevisiae is regulated by the level of intracellular S-adenosylmethionine (AdoMet). Two cis-acting elements have been previously identified within the 5' upstream regions of the structural genes of the sulfur network. The first contains the CACGTG motif and is the target of the transcription activation complex Cbflp-Met4p-Met28p. We report here the identification of two new factors, Met31p and Met32p, that recognize the second cis-acting element. Met31p was isolated through the use of the one-hybrid method, while Met32p was identified during the analysis of the yeast methionine transport system. Met31p and Met32p are highly related zinc finger-containing proteins. Both LexA-Met31p and LexA-Met32p fusion proteins activate the transcription of a LexAop-containing promoter in a Met4p-dependent manner. Northern blot analyses of cells that do not express either Met31p and/or Met32p suggest that the function of the two proteins during the transcriptional regulation of the sulfur network varies from one gene to the other. While the expression of both the MET3 and MET14 genes was shown to strictly depend upon the presence of either Met31p or Met32p, the transcription of the MET25 gene is constitutive in cells lacking both Met31p and Met32p. These results therefore emphasise the diversity of the mechanisms allowing regulation of the expression of the methionine biosynthetic genes.

scholarly journals Expert Curation of the Human and Mouse Olfactory Receptor Gene Repertoires Identifies Conserved Coding Regions Split Across Two Exons.

2019 ◽  
Author(s):  
If Barnes ◽  
Ximena Ibarra-Soria ◽  
Stephen Fitzgerald ◽  
Jose Gonzalez ◽  
Claire Davidson ◽  
...  
Keyword(s):  
Olfactory Receptor ◽  
Receptor Gene ◽  
Gene Repertoire ◽  
Coding Region ◽  
Protein Coding ◽  
Coding Sequences ◽  
Coding Regions ◽  
Or Gene ◽  
Or Genes ◽  
Human And Mouse

Abstract Olfactory receptor (OR) genes are the largest multi-gene family in the mammalian genome, with over 850 in human and nearly 1500 genes in mouse. The expansion of the OR gene repertoire has occurred through numerous duplication events followed by diversification, resulting in a large number of highly similar paralogous genes. These characteristics have made the annotation of the complete OR gene repertoire a complex task. Most OR genes have been predicted in silico and are typically annotated as intronless coding sequences. Here we have developed an expert curation pipeline to analyse and annotate every OR gene in the human and mouse reference genomes. By combining evidence from structural features, evolutionary conservation and experimental data, we have unified the annotation of these gene families, and have systematically determined the protein-coding potential of each locus. We have defined the non-coding regions of many OR genes, enabling us to generate full-length transcript models. We found that 13 human and 41 mouse OR loci have coding sequences that are split across two exons. These split OR genes are conserved across mammals, and are expressed at the same level as protein-coding OR genes with an intronless coding region. Our findings challenge the long-standing and widespread notion that the coding region of a vertebrate OR gene is contained within a single exon.

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